The present invention relates to a process for producing a xcex2-amino acid ester derivative of value as intermediates of pharmaceutical and agrochemical substances, particularly an optically active xcex2-amino acid ester derivative, and to a process for producing an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of value as its intermediates.
As the standard method of producing xcex2-amino acids from xcex1-amino acids, the process which comprises reacting a mixed acid anhydride of an xcex1-amino acid with diazomethane and causing the resulting xcex1-amino-xcex1xe2x80x2-diazoketone to undergo rearrangement in an alcohol in the presence of a metal catalyst such as silver ion (Liebigs Ann, 1995, pp.1217-122) is known. However, this process requires the use of diazomethane, an explosive and highly toxic substance, for synthesizing said xcex1-amino-xcex1xe2x80x2-diazoketone so that it is unsuited for a commercial operation.
As an alternative technology, there is known a process which comprises reducing an a-amino acid ester derivative with sodium borohydride, mesylating the resulting alcohol, reacting the mesylate with sodium cyanide, and hydrolyzing the resulting nitrile (Org. Prep Proced Int. 1994, 26(5), 599). However, this process involves many reaction steps and, in addition, requires the use of the highly toxic cyanide, thus being not suited for commercial exploitation.
In the above state of the art, the present invention has for its object to provide a commercially profitable process for synthesizing optically active xcex2-amino acid ester derivatives of value in the pharmaceutical and other fields, starting with readily available optically active xcex1-amino acid esters.
Thus, the present invention is directed to a process for producing a xcex2-amino acid ester derivative of the following formula (4): 
wherein R1 represents a substituted or unsubstituted alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms or an aryl group containing 6 to 18 carbon atoms, R3 represents an alkyl group containing 1 to 5 carbon atoms, and P1 and P2 each independently represents a hydrogen atom or an amino-protecting group or P1 and P2 taken together represents a phthaloyl group, excluding the case in which both P1 and P2 are hydrogen atoms,
which comprises reacting an xcex1-amino acid ester derivative of the following formula (1): 
wherein R1, P1 and P2 are as respectively defined above, R2 represents an alkyl group containing 1 to 5 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms,
with a base and a dihalomethane of the following formula (2):
CH2X1X2xe2x80x83xe2x80x83(2)
wherein X1 and X2 each independently represents a halogen atom, to synthesize an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of the following formula (3): 
xe2x80x83wherein R1, P1, P2, X1 and X2 are as respectively defined above,
reacting this derivative with a lithium amide and an alkyllithium in succession,
and treating the reaction product with an acid in an alcohol.
The present invention is further directed to a process for producing an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of the above general formula (3)
which comprises reacting an xcex1-amino acid ester derivative of the above formula (1) with a base and a dihalomethane of the above formula (2).
In another aspect, the present invention is directed to a process for producing a xcex2-amino acid ester derivative of the above formula (4)
which comprises reacting an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of the above formula (3) with a lithium amide and an alkyllithium in succession,
and treating the reaction product with an acid in an alcohol.
In a still another aspect, the present invention is directed to an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of the above formula (3) wherein
R1 is a benzyl group,
X1 is a bromine atom,
X2 is a chlorine atom or a bromine atom.
The present invention is now described in detail.
Referring to the above formulas (1), (3) and (4), R1 represents a substituted or unsubstituted straight-chain, branched-chain or cyclic alkyl group containing 1 to 18 carbon atoms, an aralkyl group containing 7 to 18 carbon atoms, or an aryl group containing 6 to 18 carbon atoms. As specific examples, there can be mentioned benzyl, methyl, isopropyl, isobutyl, sec-butyl and phenyl, although these are not exclusive choices. Preferred is benzyl or phenyl.
Referring to the formula (1), R2 represents an alkyl group containing 1 to 5 carbon atoms or an aralkyl group containing 7 to 12 carbon atoms. As specific examples, there can be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, benzyl, p-methylbenzyl, p-methoxybenzyl, p-nitrobenzyl and p-chlorobenzyl, among others. Preferred is methyl or ethyl.
In the formulas (1), (3) and (4), P1 and P2 each independently represents a hydrogen atom or an amino-protecting group, or P1 and P2 taken together represents a phthaloyl group; excluding the case in which both P1 and P2 are hydrogen atoms.
The amino-protecting group is not particularly restricted as far as it is a protecting group in routine use for the protection of an amino group. Thus, the groups mentioned in Protective Groups in Organic Synthesis, 2nd Ed., Theodora W. Green, John Willey and Sons), 1990, pp.309-384, e.g. methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl, t-butyloxycarbonyl, acetyl, trifluoroacetyl, benzyl, dibenzyl, phthalimido, tosyl, benzoyl, trimethylsilyl, etc., can be employed. Preferred, among these, are carbamate-form protecting groups such as, for example, methyloxycarbonyl, ethyloxycarbonyl, benzyloxycarbonyl and t-butyloxycarbonyl. When either one of P1 and P2 represents an amino-protecting group, the other preferably represents a hydrogen atom. When P1 and P2 taken together represents a phthaloyl group, it may also be regarded as a kind of amino-protecting group.
X1 and X2 in the formulas (2) and (3) each independently represents a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom. Preferred is a chlorine atom or a bromine atom. X1 and X2 may be the same or different.
R3 in the formula (4) represents a straight-chain or branched-chain alkyl group containing 1 to 5 carbon atoms. Preferred is methyl, ethyl, n-propyl or the like.
The process for producing an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative in accordance with the present invention is now described.
Thus, an xcex1-amino acid ester derivative of the formula (1) is reacted with a base and a dihalomethane of the formula (2) at xe2x88x9290xc2x0 C. to 50xc2x0 C., preferably xe2x88x9210xc2x0 C. to 30xc2x0 C., to synthesize an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative of the formula (3).
The xcex1-amino acid constituting said xcex1-amino acid ester derivative of the formula (1) is not particularly restricted but includes phenylalanine, alanine, valine, leucine, isoleucine and phenylglycine, among others. Preferred is phenylalanine or phenylglycine. In the present invention, even when an optically active amino acid is used as the starting compound, the desired compound can be obtained without decreasing in optical activity. Therefore, more preferred amino acid is L-phenylalanine or L-phenylglycine, which is optically active.
The base mentioned above is not particularly restricted but includes alkyllithiums, alkylmagnesium halides, lithium amides, e.g. lithium diisopropylamide, lithium hexamethyldisilazide, etc., and halomagnesium dialkylamides which can be prepared by reacting a Grignard reagent with a secondary amine, e.g. chloromagnesium diisopropylamide, bromomagnesium diisopropylamide and chloromagnesium dicyclohexylamide. These bases can be used independently or in a combination of 2 or more species. Preferred bases are halomagnesium dialkylamides, and particularly preferred base is chloromagnesium diisopropylamide. The amount of use of said base is 2 to 10 molar equivalents, preferably 3 to 5 molar equivalents, based on the xcex1-amino acid ester derivative.
The dihalomethane of the formula (2) is not particularly restricted but includes dichloromethane, dibromomethane and bromochloromethane, among others. Preferred is dibromomethane. The amount of use of said dihalomethane is 1 to 10 molar equivalents, preferably 1 to 3 molar equivalents, based on the xcex1-amino acid ester derivative.
The reaction solvent for use in conducting this reaction is not particularly restricted but includes ether solvents, such as diethyl ether, 1,2-dimethoxyethane, t-butyl methyl ether, tetrahydrofuran, etc.; aliphatic hydrocarbon solvents, such as hexane, pentane, etc.; and aromatic hydrocarbon solvents, such as benzene, toluene and so forth. These solvents can be used independently or in a combination of 2 or more species.
This reaction is carried out by diluting said xcex1-amino acid ester derivative and dihalomethane with the reaction solvent, then adding the base to the dilution at xe2x88x9290xc2x0 C. to 50xc2x0 C., preferably xe2x88x9210xc2x0 C. to 30xc2x0 C., and stirring the mixture for 1 to 24 hours, preferably 2 to 10 hours.
The after-treatment following the reaction comprises stopping the reaction by adding the reaction mixture to diluted hydrochloric acid, diluted sulfuric acid or an aqueous solution of ammonium chloride or the like, extracting the mixture with a suitable solvent such as ethyl acetate, diethyl ether and toluene, washing the extract serially with saturated aqueous solution of sodium hydrogencarbamate, saturated aqueous solution of sodium chloride, water and the like, followed by concentration and the routine purification procedure, e.g. recrystallization, column chromatography or the like, whereby the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone can be isolated.
Among the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivatives of the formula (3) which can be obtained by the above reaction, the derivatives of the formula (3) wherein R1 represents abenzyl group, X1 represents a bromine atom and X2 represents a chlorine atom or a bromine atom are novel compounds which have not been described in the literatures.
The process for producing a xcex2-amino acid ester derivative from an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone is now described.
Thus, the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-derivative of the formula (3) is reacted with a lithium amide and an alkyllithium in the order mentioned and the reaction product is treated with an acid in an alcohol to give the objective xcex2-amino acid ester derivative of the formula (4) In accordance with this reaction, even when the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative is an optically active compound, the objective compound can be produced without decreasing in optical activity.
The lithium amide mentioned above is not particularly restricted but includes lithium hexamethyldisilazide, lithium diisopropylamide and lithium dicyclohexylamide, among others. Preferred is lithium hexamethyldisilazide or lithium diisopropylamide. The amount of use is 2 to 5 molar equivalents, preferably 2 to 3 molar equivalents, based on the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative.
The alkyllithium mentioned above is not particularly restricted but includes methyllithium, phenyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, and n-hexyllithium, among others. Preferred is n-butyllithium. The amount of use is 1 to 10 molar equivalents, preferably 2 to 5 molar equivalents, relative to the xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone derivative.
The reaction solvent for use in conducting this reaction is not particularly restricted but includes ether solvents, such as diethyl ether, 1,2-dimethoxyethane, t-butyl methyl ether, tetrahydrofuran, etc.; aliphatic hydrocarbon solvents, such as hexane, pentane, etc.; and aromatic hydrocarbon solvents, such as benzene, toluene and so forth. These can be used independently or two or more of them can be used in combination.
The alcohol mentioned above is not particularly restricted but includes lower alcohols such as methanol, ethanol, n-propyl alcohol, etc. Preferred is methanol or ethanol. The alkyl moiety of this alcohol corresponds to R3 in the formula (4).
The acid for use in the above treatment is not particularly restricted but hydrogen chloride and sulfuric acid can be mentioned as preferred examples.
This reaction is carried out be reacting an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone of the formula (2) with said lithium amide at xe2x88x9290xc2x0 C. to 20xc2x0 C., preferably xe2x88x9280xc2x0 C. to 50xc2x0 C., for 10 minutes to 180 minutes, preferably 30 to 60 minutes, and then reacting it with said alkyllithium at xe2x88x9290xc2x0 C. to 20xc2x0 C., preferably xe2x88x9280xc2x0 C. to xe2x88x9250xc2x0 C., for 10 to 180 minutes, preferably 30 to 60 minutes, and adding the reaction mixture to an alcohol containing said acid.
The after-treatment may for example comprise adding water to stop the reaction, extracting the mixture with a solvent such as ethyl acetate, diethyl ether, toluene or the like, washing the extract with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium chloride, water and the like, followed by concentration and isolation by the routine procedure such as recrystallization, chromatography and/or the like, whereby the xcex2-amino acid ester derivative can be isolated.
As an alternative, the xcex2-amino acid ester derivative of the formula (4) can be directly obtained by reacting an xcex1-amino acid ester derivative of the formula (1) with a dihalomethane of the formula (2) and a base in the same manner as above to synthesize an xcex1-amino-xcex1xe2x80x2,xcex1xe2x80x2-dihaloketone of the formula (3) and, without quenching the reaction, reacting it further with said lithium amide and alkyllithium in succession, followed by said acid treatment in an alcohol.